Synthesis and biological activity of pyrazolothienotetrahydroisoquinoline and [1,2,4]triazolo[3,4-a]thienotetrahydroisoquinoline derivatives

1-Hydrazino-3-thioxo-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (3) was subjected to react with bifunctional compounds namely: acetylacetone, ethyl cyanoacetate, ethyl benzoylactate, diethylmalonate and ethyl acetoacetate to produce pyrazololthienotetrahydroisoquinoline derivatives 6-11. Also, heating of compound (3) with formic acid afforded triazolothienotetrahydroisoquinoline compound 5 which reacted with α-halogenated compounds to afford compounds 13a-e. Compound 13c when heated with triethylorthoformate afforded triazolo derivative 14. Also, compound 6 was used for synthesizing compounds 18-20. Representative compounds of the synthesized triazolo and pyrazolothienotetrahydroisoquinoline products were tested and evaluated as antimicrobial agents.     

Synthesis and biological activity of dihydroimidazole and 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazins

Reaction of 2-guanidinobenzimidazole with halogenated active methylenes and ketones gave dihydroimidazole and 3,4-dihydrobenzo[4,5]imidazo [1,2-a][1,3,5]triazin derivatives in very good yield. The anti-bacterial evaluation of the newly synthesized products against broad spectrum of bacteria was performed. Most of products showed high inhibitory effect. All compounds have been characterized based on IR, (1)H NMR, (13)C NMR and Mass spectra.     

Synthesis and biological activity of new derivatives of 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid

New 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid derivatives (8-14) were synthesized by condensation of N(3)-substituted amidrazones (1-7) with maleic anhydride. Molecular structure of obtained compounds was confirmed by an elemental analysis, IR and (1)H NMR spectra, and the X-ray crystallography for compound 11. The influence of the compound 9 on the central nervous system (CNS) of mice in some behavioural test was examined. The investigated compound showed anticonvulsive activity and potent antinociceptive action.     

Design, synthesis and biological activity of acyl substituted 3-amino-5-methyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones as potential hypnotic drugs

Among the known non-benzodiazepinic hypnotic drugs acting on the alpha1 subunit of the GABA-A receptor, Zolpidem, Zaleplon and Indiplon have showed high affinity and selectivity. Following a design methodology including pharmacophoric requirements and ADME-predicted properties, we have synthesized a library of 3-amino-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones and their N1-alkyl derivatives as new scaffolds for designing non-benzodiazepine BZ receptor ligands.     

Serum lipoprotein(a) [Lp(a)] in alcoholic men: Effect of withdrawal

This study examines the effect of alcohol withdrawal on lipoprotein(a) [Lp(a)] in 24 male, middle-aged chronic alcohol abusers admitted for withdrawal therapy. Serum concentration of Lp(a) was determined before and during the first 3 weeks of abstinence. The changes in three sialylated proteins [Lp(a), α1-antitrypsin (α1-AT), and haptoglobin (Hp)] and in desialylated transferrin (CDT) were also determined in 14 patients. After the 3 weeks of withdrawal therapy, the mean and median Lp(a) concentrations increased (p = 0.0001). The changes in Lp(a) levels were not related to the changes in dietary intake nor to the decrease in total HDL, HDL₃, HDL₂ cholesterol, Apo A-I, and Apo B. In the subgroup of 14 chronic alcohol abusers, Lp(a) levels increased parallel with Hp and α1-AT, whereas CDT decreased. It is concluded that the impact of alcohol on sialylated proteins may be one of the mechanisms responsible for the increase in plasma Lp(a) after alcohol withdrawal.     

Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives

Acetic acid ethyl esters containing 5-oxo-[1,2,4]triazole ring (2) were synthesized by the condensation of compounds 1a-f with ethyl bromoacetate in basic media. The reaction of compounds 2a-f with hydrazine hydrate led to the formation of acid hydrazides (3a-f). The treatment of compounds 3 with two divers aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (4a,c,e,f, 5a,e,f). The thiosemicarbazide derivatives (6a,c,d,f) were afforded by the reaction of corresponding compounds 3 with phenylisothiocyanate. The treatment of compounds 6a,c,d,f with sulfuric acidic caused the conversion of side-chain of compounds 6a,c,d,f into 1,3,4-thiadiazol ring; thus, compounds 7a,c,d,f were obtained. On the other hand, the cyclization of compounds 6a,c,d,f in the presence of 2 N NaOH resulted in the formation of compounds 8a,c,d,f containing two [1,2,4]triazole rings which are linked to each other via a methylene bridge. Compounds 4a, f, 5a, 7a, d, f, 8a and d have shown antimicrobial activity against one or more microorganism, but no antifungal activity has been observed against yeast like fungi. Also inhibitory effect on mycelial growth by compounds 4e, 7d and 8f has been observed. Compounds 4c and 5f were found to possess antitumor active towards breast cancer.     

Pregnancy interceptive efficacy and biological profile of 3-amino-6,7-dimethoxy-1H-pyrazolo [3,4-b] quinoline (compound 85/83) in rodents

Administration of compound 85/83 during the peri- and post-implantation period intercepted pregnancy in hamster and guinea pig by parenteral route and in hamster by oral route also. The m.e.d. for hamster and guinea pig was 10 and 20 mg/kg, respectively; lower doses were less effective. Restricting the administration to early post-implantation schedule interrupted pregnancy partially in both species. The compound was, however, ineffective in rat and in the pre-implantation schedule (days 1-4 post-coitum) in hamster. When tested in vitro on growing trophoblasts at 13.8 x 10(-5) M concentration, it prevented growth and caused degeneration of the cells within 24 h; lower concentration (9.2 x 10(-5) M) was less effective. The compound was found to be devoid of estrogenic, antiestrogenic, progestational and antiprogestational properties in conventional bioassays. In hormone competition assays, its relative binding affinity (RBA) to estrogen receptor was negligible (0.002% of estradiol-17 beta), while for uterine cytosol progesterone receptors in rabbit and hamster was 0.06 and 0.08% of progesterone, respectively. The compound 85/83 appears to intercept pregnancy by interfering with development of trophoblast cells.     

Synthesis, characterisation, activities, cell uptake and DNA binding of [[trans-PtCl(NH3)2] [mu-(H2N(CH2)6NH2)] [trans-PdCl(NH3)2](NO3)Cl

The dinuclear complex: [[trans-PtCl(NH(3))(2)] [mu-(H(2)N(CH(2))(6)NH(2))] [trans-PdCl(NH(3))(2)](NO(3))Cl (code named DHD) has been synthesized and characterized. The activity against human cancer cell lines including ovarian: A2780, A2780(cisR), cell up take, level of binding with DNA and nature of interaction of the compound with pBR322 plasmid and salmon sperm DNAs have been determined. The compound is found to exhibit significant anticancer activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R)--about two times as active as cisplatin against A2780 cell line, about five times as active as cisplatin against A2780(cisR) and A2780(ZD0473R) cell lines. The higher activity of DHD suggests that the compound is able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. DHD is believed to form a range of interstrand GG adducts with duplex DNA that induces global changes in the DNA conformation, unlike cisplatin and ZD0473 that form mainly intrastrand adducts that induces a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of DHD provides support to the idea that the interstrand binding of DHD with pBR322 plasmid DNA brings about global changes in DNA conformation.     

Synthesis and antibacterial activity of some 5-(4-biphenylyl)-7-aryl[3,4-d] [1,2,3]-benzothiadiazoles

A series of 5-(4-biphenylyl)-7-aryl[3,4-d] [1,2,3]-benzothiadiazoles were synthesized, characterized by IR, NMR and elemental analysis and evaluated for in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria. The antibacterial data revealed that compounds 7a-j had better activity against tested Gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against Gram-negative bacteria. Compound 7c and 7d were the most active compounds against Gram-positive bacteria.     

Synthesis and biological activity of 1beta-methyl-2-[5-(2-N-substituted aminoethylcarbamoyl)pyrrolidin-3-ylthio]carbapenem derivatives

The synthesis of a new series of 1beta-methylcarbapenems having the substituted aminoethylcarbamoylpyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. In particular, the compound 11g having piperazinyl urea moiety showed the most potent antibacterial activity and 11k exhibited excellent anti-MRSA.     

Synthesis and antibacterial activity of bis-[2-hydroxy-3-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-aza-tricyclo[5.2.1.0(2,6)]dec-8-en-4-yloxy)-propyl]-dimethyl-ammonium chloride

A new quaternary ammonium compound, bis-[2-hydroxy-3-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-aza-tricyclo[5.2.1.0(2,6)]dec-8-en-4-yloxy)-propyl]-dimethyl-ammonium chloride (4), was synthesized. The compound was investigated for antibacterial activity, including Gram-positive cocci and Gram-negative rods, and antifungal activity. Compound 4 showed significant inhibition against Staphylococcus aureus. Research was carried out over 4 standard strains and 40 hospital strains. Elementary analysis and/or MS, (1)H NMR and (13)C NMR spectra confirmed the identity of the products. The molecular structure of 3 was determined by an X-ray analysis.     

Synthesis of quaternised 2-aminopyrimido[4,5-d]pyrimidin-4(3H)-ones and their biological activity with dihydrofolate reductase

In a program to design and develop mechanism-based compounds active as substrates and inhibitors of dihydrofolate reductase (DHFR), we report the synthesis and physical properties of the 6-methyl- (7), 8-methyl- (8a), and 8-ethyl- (8b) derivatives of the parent 2-aminopyrimido[4,5-d]pyrimidin-4-(3H)-one (6). These compounds are the first members of a class of heterocycles related to 8-alkylpterins (N8-alkyl-2-aminopteridin-4(8H)-ones) (2a-2c), which have been shown to be novel substrates for DHFR. Three methods were developed for the synthesis of target compounds 7, 8a and 8b; however, the optimum yields (1-8%) could not be improved because the products decomposed by ring opening (e.g. to 2,4-diamino-5-methyliminomethylpyrimidin-6(1H)-one (9)) under the reaction conditions. The marked pi-electron deficiency of compounds 7, 8a and 8b is the likely cause for the susceptibility of the quaternised pyrimidine ring in the related cations 10, 15a and 15b, respectively, to add nucleophiles, thus promoting the opening of the pyrimidopyrimidine ring system. 1H-NMR spectroscopic studies of compounds 7, 8a and 8b revealed a fast and reversible covalent hydration of the associated cations across the C7z.sbnd;N8 bond for the N6-methyl derivative 7 and across the N6z.sbnd;C7 bond for the N8-methyl derivative 8a. UV spectroscopic studies of methyl derivatives 7 and 8a as well as the parent heterocycle 6 showed that protonation of the latter occurred at N1, while methylation with iodomethane proceeded at N6 and N8. The basicities of the N-methyl derivatives 7 and 8a (pK(a) ca. 5.5) are similar to those of 8-alkylpterins 2; this is an essential element of the design to promote binding to DHFR in their protonated form. Enzyme kinetics of 7, 8a and 8b with chicken DHFR confirmed our predictions that they are substrates, with apparent K(m) values of 3.8, 0.08, and 0.65 mM, and apparent V(max) values of 0.47, 2.27, and 0.30 nmol L(-1) min(-1) (for enzyme concentration 0.122 micro M), respectively. The parent compound 6 was not a substrate.     

The uptake, metabolism, and biological half-life of benzo[a]pyrene administered by force-feeding in sea bass (Dicentrarchus labrax).

The kinetics of uptake and metabolism of benzo[a]pyrene (BaP) were studied in various tissues of a marine fish, the sea bass (Dicentrarchus labrax), after intragastric administration of pellets containing a 14C-labeled compound. Only 25% of injected radioactivity was detected and it was found only in intestine, gallbladder, liver, and kidney. The major part of radioactivity was found in gallbladder (85% of the whole body radioactivity). The calculated half-lives determined after the decrease in radioactivity measured in these tissues were 8.2, 3.5, 3.3, and 0.8 days for liver, gallbladder, intestine, and kidney, respectively. The kinetics of distribution of radioactivity between alkali and hexane tissue extracts showed the high metabolization potential of intestine which represents the main site of BaP uptake by this route of exposure. The other organs received mainly metabolites brought by general blood circulation. Intragastric administration as an experimental exposure route compared to other exposure patterns and particularly intraperitoneal injection, which has been used previously in the same species and under the same experimental conditions for the same kind of study, is discussed.     

Synthesis of N-(5,7-diamino-3-phenyl-quinoxalin-2-yl)-3,4,5-substituted anilines and N-[4[(5,7-diamino-3-phenylquinoxalin-2-yl)amino]benzoyl]-l-glutamic acid diethyl ester: evaluation of in vitro anti-cancer and anti-folate activities

Several diamino quinoxalines were designed, synthesized and evaluated as anti-tumor agents. Two compounds showed the most potent cytotoxic activities against the leukemia CCRF-CEM cell line (GI(50)<0.01microM) and the ovarian cancer cell line OVCAR-4 (GI(50)=0.03microM), respectively, with comparable/better activities than Methotrexate (MTX). Docking calculations of the complexes of hDHFR with the most active compounds identified the binding mode of the described molecules with respect to MTX.     

Synthesis, antitrichinnellosis and antiprotozoal activity of some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazole ring

Some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazol-2-yl-thioethyl- and benzimidazol-2-yl-methanethioethyl moiety in second position of the pyrimidine ring were synthesized in order to determine their antitrichinellosis and antiprotozoal effects. The structures of the compounds were confirmed by IR, (1)H NMR and elemental analysis. The antiparasitic screening showed that the benzimidazole derivatives of thieno[2,3-d]pyrimidin-4(3H)-ones exhibited higher activity against Trichinella spiralis in vitro in comparison albendazole. The most active compound, 2-[2-(5-nitro-1H-benzimidazol-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one 22 revealed 95% activity at a dosage of 5?mg/kg?mw after 24?h, while compounds 8 and 10 applied at the same dose showed efficacy of 90% after 48?h. The compound 2-{2-[(5(6)-nitro-1H-benzimidazol-2-yl)thio]ethyl}-5,6,7,8-tetrahydro[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one 11 exhibited 90% efficacy after 24?h. The pharmaco-therapeutic study in vivo on invaded with Lamblia muris white mice showed 100% effectiveness of the compounds 8, 10, 11, 13-15 and 22, 23 after five-days-treatment course.     

Comparison of the spermicidal activity and acute toxicity of nonoxynol-9 and agent 741 [alkylphenoxy polyethoxy ethanol(10)]

A spermicidal agent called "741" is used in the People's Republic of China as a substitute for nonoxynol-9 in vaginal contraceptive preparations. The relative spermicidal activity of these two agents was evaluated using dog, rabbit, monkey and human semen. Acute LD50 determinations in mice were also performed. The spermicidal activity and acute toxicity of both agents were either identical or very similar in all species. Since agent 741 is less expensive than nonoxynol-9 to manufacture and equally as potent in vitro, it is an alternative spermicide for vaginal contraceptive formulations.     

Heterocyclic system containing bridgehead nitrogen atom: synthesis and pharmacological activities of some substituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles

Several 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadizoles were prepared by the condensation of 4-amino-3-aryl/aralkyl substituted-5-mercapto-1,2,4-triazoles 3(a-c) with various substituted aromatic/hetero aromatic acids through a single step reaction. Elemental analysis, IR, 1H NMR and mass spectral data confirmed the structure of the newly synthesized compounds. Synthesized triazolo thiadiazoles investigated for their antibacterial, antifungal, anti-inflammatory and analgesic activities. Some of the tested compounds showed moderate antimicrobial activity against various tested bacterial and fungal strains. None of the synthesized compounds have significant anti-inflammatory and analgesic activities.     

Dietary docosahexaenoic acid [22: 6(n-3)] as a phospholipid or a triglyceride enhances the potassium chloride-evoked release of acetylcholine in rat hippocampus

We demonstrated previously that a dietary-induced depletion of docosahexaenoic acid (DHA) in cerebral phospholipids increases the spontaneous release of acetylcholine (Ach) in the rat hippocampus and reduces its potassium chloride evoked-release. In the present study, we investigated the effects in rats of DHA-enriched diets supplied by egg phospholipids (E-PL) or tuna oil (TO) on the PUFA in hippocampus membranes and on the synaptic release of Ach. Control rats were fed 3 g/kg of the DHA precursor, alpha-linolenic acid (LNA). Chronically (n-3) PUFA-deficient females were fed, starting 2 wk before mating, the deficient diet, a control diet, or a purified diet supplying 1, 2, or 3 g DHA/kg diet as E-PL or TO. Experiments were performed on the adult male progeny fed the same diet as their dams throughout life. The form of dietary DHA (TO or E-PL) did not influence its incorporation into the hippocampus. The 1 g DHA/kg diets allowed maximal incorporation into phosphatidylethanolamine (PE), but 2 g DHA/kg diet was needed for phosphatidylcholine (PC). A minimum of 2 g DHA/kg was needed to decrease the basal Ach release and to enhance the stimulated release to that of the control; the Ach release of the 1 g/kg DHA-groups did not differ from that of the deficient group. This suggests that >1 g DHA/kg diet is needed to ensure PUFA incorporation into PE and PC, and basal and stimulated Ach release in the rat hippocampus equivalent to the control group fed only LNA. PUFA incorporation into the hippocampus depends mainly on the PUFA concentration of the diet, not on the form of dietary DHA.     

Synthesis and biological activity of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors

A series of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented.Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.